The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Gliomas arise from glial cells that are present in the brain and spinal cord. Gliomas are named according to their clinicopathologic and histologic subtype. For example, astrocytomas originate from astrocytes, oligodendroglial tumors from oligodendrocytes, and mixed gliomas from a mix of oligodendrocytes, astrocytes, and ependymal cells. Astrocytoma is the most commonly diagnosed type of glioma in children. According to the WHO classification of brain tumors, gliomas are further classified as low-grade (grades I and II) and high-grade (grades III and IV) tumors. Children with low-grade tumors have a relatively favorable prognosis, especially when the tumors can be completely resected. Children with high-grade tumors generally have a poor prognosis, unless the tumor is an anaplastic astrocytoma that can be completely resected.
Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer toTable 3 for the most common CNS location for each tumor type.
Presenting symptoms for childhood astrocytomas depend on the following:
Size of the tumor.
Rate of tumor growth.
Chronologic and developmental age of the child.
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.
The diagnostic evaluation for astrocytoma is often limited to a magnetic resonance imaging (MRI) of the brain or spine. Additional imaging, when clinically indicated, would consist of an MRI of the remainder of the neuraxis.
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Examination of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Tumor types are based on the glial cell type of origin:
Oligodendroglial tumors (oligodendrocytes).
Mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells).
Mixed neuronal-glial tumors.
WHO histologic grade
According to the WHO histologic typing of CNS tumors, childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are graded (grade I to IV).
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).
Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System
WHO Histologic Grade
Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial Origin
WHO Histologic Grade
aIn 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. It was determined that the pilomyxoid variant of pilocytic astrocytoma may be an aggressive variant that is more likely to disseminate, and it was reclassified as a grade II tumor.[1,2,5]
Subependymal giant cell astrocytoma
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have common CNS locations (refer to Table 3).
Table 3. Common Central Nervous System (CNS) Locations for Childhood Astrocytomas and Other Tumors of Glial Origin
Common CNS Location
Optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem; and spinal cord (rare)
Superficial location in cerebrum (temporal lobe preferentially)
Diffuse astrocytoma (including fibrillary)
Cerebrum (frontal and temporal lobes), brain stem, spinal cord, optic nerve, optic chiasm, optic pathway, hypothalamus, and thalamus
Anaplastic astrocytoma, glioblastoma
Cerebrum; occasionally cerebellum, brain stem, and spinal cord
Cerebrum (frontal lobe preferentially followed by temporal, parietal, and occipital lobes), cerebellum, brain stem, and spinal cord
Cerebral hemispheres (frontal lobe preferentially followed by the temporal lobe)
Cerebrum with or without brain stem involvement, cerebellum, and spinal cord
More than 80% of astrocytomas located in the cerebellum are low grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1,2] The presence of certain histologic features (e.g., MIB-1 rate, anaplasia) has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[6-8]
Astrocytomas arising in the brain stem may be either high grade or low grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[9,10] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely high-grade gliomas (e.g., diffuse intrinsic pontine gliomas).[9,10] (Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for more information.)
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum.[11,12] Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred.
Gliomatosis cerebri is a diffuse glioma that involves widespread involvement of the cerebral hemispheres in which it may be confined, but it often extends caudally to affect the brain stem, cerebellum, and/or spinal cord. It rarely arises in the cerebellum and spreads rostrally. The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.
Neurofibromatosis type 1 (NF1)
Children with NF1 have an increased propensity to develop WHO grade I and grade II astrocytomas in the visual (optic) pathway; approximately 20% of all patients with NF1 will develop an optic pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits.
Pathologic confirmation is frequently not obtained in asymptomatic patients; when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than fibrillary (grade II) astrocytomas.[2,5,15-17]
In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.
Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[19-23] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[19,20,24-28]
Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas. However, other factors such as p16 deletion and tumor location may modify the impact of the BRAF mutation on outcome. Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.
BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[27,28]
Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, andBRAF V600E point mutations) are less commonly observed.[20,22,23,31] BRAF V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytoma cases.[32-34] One retrospective study of 53 children with gangliogliomas demonstrated BRAF V600E staining in approximately 40% of tumors. Five-year recurrence-free survival was worse in the V600E-mutated tumors (about 60%) than in tumors that did not stain for V600E (about 80%). The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of mutation in cases that did not transform (10 of 167 cases).
As with neurofibromatosis type 1 (NF1) deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.
Activating mutations in FGFR1, PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas. In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[37,38]
Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules.
Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[39-42] Pediatric high-grade gliomas have PTEN and EGFRgenomic alterations less frequently and PDGF/PDGFR genomic alterations and mutations inhistone H3.3 genes more frequently than do adult tumors. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondaryglioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have IDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.[43-45]
Based on epigenetic patterns (DNA methylation), pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups with distinctive chromosome copy number gains/losses and gene mutations.
Two subgroups have identifiable recurrent H3F3A mutations, suggesting disrupted epigenetic regulatory mechanisms, with one subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34). The subgroups are the following:
H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brainstem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.
H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome.
The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors. Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[43-45,47,48]
Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA andmesenchymal clusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are predominantly composed of cortical tumors, with cerebellar glioblastoma multiforme tumors rarely observed; both subtypes have a poor prognosis.
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven (approximately 40%) of 18 patients with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 (57%) of 14 cases.
The molecular profile of pediatric patients with oligodendrogliomas rarely demonstrates deletions of 1p and 19q, as found in 40% to 80% of adult cases. Similarly, IDH1 mutations are also uncommon. When 1p19q codeletion or IDH1 mutations are present in pediatric oligodendroglioma, they are observed primarily in patients older than 15 years.[37,49,50] Like other diffuse pediatric low-grade gliomas, pediatric oligodendrogliomas were noted to have FGFR1 tyrosine kinase domain duplications (3 of 5 cases studied), with an MYB fusion gene observed in one of the two remaining cases.
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[11,12,51-55] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[56,57] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.
Unfavorable prognostic features for childhood low-grade astrocytomas include the following:[58-60]
Inability to obtain a complete resection.
Intracranial hypertension at initial presentation.
In patients with pilocytic astrocytoma, elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS. A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.
Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the optic pathway.[61-64]; [Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[61,66]
Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[5,67,68] MIB-1 labeling index is predictive of outcome in childhood malignant brain tumors. Both histologic classification and proliferative activity evaluation have been shown to be independently associated with survival.
Although high-grade astrocytomas generally carry a poor prognosis in younger patients, those with anaplastic astrocytomas in whom a gross-total resection is possible may fare better.[53,70,71]
Oligodendrogliomas are rare in children and have a relatively favorable prognosis; however, children younger than 3 years who have less than a gross-total resection have a less favorable prognosis.
This summary does not address the treatment of children with oligodendrogliomas.
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